Cystinuria: genetic aspects, mouse models, and a new approach to therapy
Cystinuria, a genetic disorder of cystine transport, is characterized by excessive excretion of cystine in the urine and recurrent cystine stones in the kidneys and, to a lesser extent, in the bladder. Males generally are more severely affected than females. The disorder may lead to chronic kidney disease in many patients. The cystine transporter (b0,+) is a heterodimer consisting of the rBAT (encoded by SLC3A1) and b0,+AT (encoded by SLC7A9) subunits joined by a disulfide bridge. The molecular basis of cystinuria is known in great detail, and this information is now being used to define genotype–phenotype correlations. Current treatments for cystinuria include increased fluid intake to increase cystine solubility and the administration of thiol drugs for more severe cases. These drugs, however, have poor patient compliance due to adverse effects. Thus, there is a need to reduce or eliminate the risks associated with therapy for cystinuria. Four mouse models for cystinuria have been described and these models provide a resource for evaluating the safety and efficacy of new therapies for cystinuria. We are evaluating a new approach for the treatment of cystine stones based on the inhibition of cystine crystal growth by cystine analogs. Our ongoing studies indicate that cystine diamides are effective in preventing cystine stone formation in the Slc3a1 knockout mouse model for cystinuria. In addition to crystal growth, crystal aggregation is required for stone formation. Male and female mice with cystinuria have comparable levels of crystalluria, but very few female mice form stones. The identification of factors that inhibit cystine crystal aggregation in female mice may provide insight into the gender difference in disease severity in patients with cystinuria.
KeywordsCystinuria Cystine Transport defect Mouse models Crystal growth inhibitors Therapeutics
This work was supported in part by the Human Genetics Institute of New Jersey and by NIH Grant R01DK112782.
Compliance ethical standards
Conflict of interest
Dr. Goldfarb has received consulting fees from Retrophin. The other authors declare that they have no relevant financial interests. The work described in this manuscript on cystine diamides has been licensed by Rutgers University to PharmaKrysto. Rutgers University is the assignee of Patent Number US 9,248,453 B2 entitled “Cystine diamide analogs for the prevention of cystine stone formation in cystinuria” and New York University is the assignee of Patent Number US 8,450,089 B2 entitled “Compounds as L-cystine crystallization inhibitors and uses thereof”.
All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Rutgers University.
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